Development of long-acting injectable suspensions by continuous antisolvent crystallization: An integrated bottom-up...

Area of Science:

• Pharmaceutical Technology
• Materials Science
• Chemical Engineering

Background:

• Developing stable long-acting injectable (LAI) suspensions for poorly soluble drugs like itraconazole (ITZ) presents significant formulation challenges.
• Traditional methods often involve complex multi-step processes that can be difficult to scale and control.
• A continuous, integrated approach is needed for efficient and reproducible LAI suspension manufacturing.

Purpose of the Study:

• To establish the operational feasibility of directly generating and stabilizing long-acting injectable (LAI) itraconazole (ITZ) suspensions.
• To develop a continuous crystallization process using a microchannel reactor combined with downstream processing.
• To optimize parameters for producing a stable, high-concentration ITZ LAI suspension with controlled particle size.

Main Methods:

• A novel microchannel reactor (MCR)-based continuous liquid antisolvent crystallization setup was designed and optimized.
• N-methyl pyrrolidone (NMP) was identified as the optimal solvent, and process parameters (S/AS ratio, flow rates, concentration, maturation time) were tailored.
• Downstream processing included centrifugal filtration and reconstitution with Vitamin E TPGS as a stabilizer, followed by in vitro release studies.

Main Results:

• The optimized process yielded an ITZ LAI suspension (300 mg/mL) with a desirable particle size distribution (D10=1.1, D50=3.53, D90=6.5 µm).
• The suspension demonstrated remarkable stability, remaining unchanged for 548 days at 25°C.
• Vitamin E TPGS (0.5% w/w) proved to be the most effective stabilizer among 14 screened excipients.

Conclusions:

• The integrated continuous crystallization and downstream processing approach is operationally feasible for producing stable ITZ LAI suspensions.
• This bottom-up manufacturing strategy provides a scalable and reproducible framework for developing LAI drug delivery systems.
• The study offers valuable guidance for the development of LAI suspensions using itraconazole as a model active pharmaceutical ingredient (API).